Action Points

A third randomized trial presented at the meeting -- RODEO -- confirmed reduced systemic inflammation with short-term treatment with rosuvastatin in stable COPD patients without known cardiovascular disease, but showed no benefit for pulmonary function.

Putting patients on the lipid-lowering drug actually contributed to hepatic and renal failure, Jonathon D. Truwit, MD, of the Medical College of Wisconsin in Milwaukee, and colleagues found in the ARDS Clinical Trials Network study.

In the STATCOPE trial, simvastatin (Zocor) didn't prevent COPD exacerbations compared with placebo (1.36 versus 1.39 mean per person-year, P=0.54) or delay them (median 223 versus 231 days to first exacerbation, P=0.34), Gerard Criner, MD, of Temple University in Philadelphia, reported at the meeting.

Both National Heart, Lung, and Blood Institute-sponsored trials were reported at a late-breaking clinical trials session here at the American Thoracic Society meeting and released simultaneously online in the New England Journal of Medicine.

A Worthwhile Strike-Out?

Despite striking out, the trials weren't a waste of public funds, Jeffrey M. Drazen, MD, editor-in-chief of that journal, and Annetine C. Gelijns, PhD, of Mount Sinai School of Medicine in New York City, argued in an accompanying editorial.

"In both diseases, our therapeutic armamentarium is meager, the public health need is great, and the intervention was reasonable and had face validity," they wrote.

There was a solid rationale for both that the pleomorphic anti-inflammatory effects of statins would pay off in the conditions for which inflammation is thought to drive disease pathobiology, the editorial noted.

A third randomized trial presented at the meeting -- RODEO -- confirmed reduced systemic inflammation with short-term treatment with rosuvastatin in stable COPD patients without known cardiovascular disease.

But again it showed no benefit for pulmonary function, Anke Neukamm, MD, of Akershus University Hospital in Oslo, Norway, and colleagues found.

In the 99-patient trial, 10 mg rosuvastatin daily for 12 weeks reduced high-sensitivity C-reactive protein and cut the rise in interleukin-6 as markers of inflammation compared with placebo (P=0.017 and P=0.028, respectively).

But lung function as measured by forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity showed no difference between groups (P=0.462 and P=0.292).

Observational studies had suggested better outcomes in patients on statins in both COPD and sepsis.

Despite the negative results in the randomized trials, "they had to be done," Drazen and Gelijns wrote. "It would have been a big mistake to accept the findings without a test."

This kind of "discovery-in-practice" route to clinical trials is likely to be increasingly seen as electronic health records are exploited for big data, they noted.

Statins for ARDS in Sepsis

The ARDS trial was stopped for futility after 745 of the planned 1,000 patients had been enrolled at 44 participating hospitals.

Participants were randomized to a 40-mg loading dose of either rosuvastatin or placebo within 48 hours of onset of ARDS and then daily maintenance dosing at 20 mg, or 10 mg for those with elevated serum creatinine levels not on renal-replacement therapy.

Treatment continued for up to 28 days but was stopped early in case of ICU discharge, hospital discharge, or death.

Nor were there differences in the primary endpoint of mortality before hospital discharge home or until study day 60 if the patient was still in a healthcare facility for the subgroup of patients in shock at baseline (36% on statin versus 32% on placebo, P=0.39), or in those who used a statin before their critical illness (31% versus 20%, P=0.14).

While rosuvastatin wasn't associated with higher incidence of serum creatine kinase levels over 10 times the upper limit of normal, it did result in fewer days free of renal failure to day 14 (10.1 versus 11.0, P=0.01) and fewer days free of hepatic failure to day 14 (10.8 versus 11.8, P=0.003).

"These differences in organ-failure-free days were small, and their significance may be spurious owing to the number of secondary end points analyzed," Truwit's group cautioned. "However, we cannot rule out a detrimental effect of rosuvastatin."

The study used a moderate statin dose selected for its potentially fewer drug interactions. But it didn't achieve the expected plasma levels of the drug, which could have accounted for the lack of efficacy, they suggested.

Given the signs of potential toxicity, though, higher doses might not have been appropriate, they argued.

"These results, coupled with those of smaller randomized trials of other statins, do not provide support for initiating or continuing statin therapy for the treatment of sepsis-associated ARDS," Truwit's group concluded.

Perhaps the observational findings of benefit had been due to confounding from better access to healthcare and thus earlier initiation of antibiotics in patients who come in on statins, or statins have preventive effects when taken long-term before infection that couldn't be replicated short-term after infection, they suggested.

Statins for COPD

Preventive use of simvastatin for COPD also didn't pan out in STATCOPE (Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations), according to Criner and colleagues.

The trial was halted early for futility after enrolling 878 patients with moderate to severe COPD, a smoking history of 10 or more pack-years, on supplemental oxygen or treatment with glucocorticoids or antibiotics, or an emergency department visit or hospitalization for COPD within the prior year.

Randomization to simvastatin at a daily dose of 40 mg didn't impact the primary endpoint of annual exacerbation rates in any patient subgroup.

Nor did the drug improve lung function as assessed spirometrically, or general or respiratory-specific quality of life.

Deaths and other serious adverse events came out similar between groups, too.

The study excluded patients with diabetes or cardiovascular disease and those who were taking statins or who should have been based on national guidelines.

That may have explained the difference between the trial results and those of previous positive studies, Criner's group suggested.

"The underuse of statins in persons with cardiac risk factors who have been included in retrospective studies may account in part for the differences between our findings and those previously reported," they wrote.

They called their findings conclusive, while acknowledging it wasn't clear whether the results would generalize to less severe COPD.

Another limitation was that the trial didn't use a marker of systemic inflammation, like serum C-reactive protein (CRP) to screen for enrollment, which "may have limited our ability to detect an effect of simvastatin in reducing the rate of exacerbations," they noted.

STATCOPE was funded by the National Heart, Lung, and Blood Institute (NHLBI) and the Canadian Institutes of Health Research.

Truwit's trial was funded by the NHLBI and the Investigator-Sponsored Study Program of AstraZeneca.

MedPageToday is a trusted and reliable source for clinical and policy coverage that directly affects the lives and practices of health care professionals.

Physicians and other healthcare professionals may also receive Continuing Medical Education (CME) and Continuing Education (CE) credits at no cost for participating in MedPage Today-hosted educational activities.